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Duration
The length of time an insulin remains active in the system. Since activity decays on a half-life curve, there is no actual hard time when duration has ended -- it's a matter of degree. The usual time used for reference is either whatever the manufacturer claims, or the time when blood glucose levels have reached the same point they were at shot time. Any residual effect of the insulin beyond that time is carryover. Duration is also quite individual--can vary from patient to patient and even with the same patient. The insulin time activity profilesHow Insulin Time Activity Profiles Are CreatedAbsorption Kinetics of Regular (Neutral) & Isophane (NPH) Insulin in the Normal Dog-Domestic Animal Endocrinology-1987Establishment of Time-Action Profiles for Regular (Neutral) NPH (Isophane) Insulin Using Pharmacodynamic Modeling-Diabetes Care-ADA-1994 you see are basically averages of blood glucose levels in a test group or groups of patients for a given time period. Some tested patients experienced longer than average duration, while for others it was less than average. Many of the duration test results done by manufacturers of human approved insulins are based on two patient groups--those with diabetes and non-diabetics who agreed to assist in the study. This combined and averaged data is used to generate the time activity profile. It means that there are VERY few with diabetes whose personal insulin activity profile is a perfect replica of those displayed. It follows then, that onset and peak times found on insulin time activity profiles are just as subject to variability as is duration, since they are all obtained in the manner above. Duration varies by species and strength, in addition to type. With regard to the non-analog insulins, duration can also be influenced by the size of the insulin dose itself, with larger doses having a stronger effect and a longer duration than smaller onesInsulin-Dependent Diabetes--Dr. Ragnar Hanas (Page 6). Duration Problems Short Duration This is a blood glucose graph of a cat who is receiving one shot of Bovine (beef) Lente insulin daily. After the 8 hour point, blood glucose values begin climbing. Interestingly enough, the insulin peak is within acceptable values. This insulin is working for this cat, but he/she is not getting enough duration from only one shot a day. Note: blood glucose values are shown in mmol/l (non-US) measurements. From what's seen here, it would appear that there this is a problem which can be easily solved by increasing from one-daily to twice daily doses of the Bovine (beef) Lente. There appears not to be any Insulin resistance but just a matter of the Intermediate-acting beef Lente not providing adequate control when given only once a day. http://www.vin.com/ImageDBPub/TN20000/TN_IMC16197_550X0Y.jpg In contrast, let's look at a blood glucose graph of an animal who is being given Lente insulin twice daily, but has resistance to it. (Note: species of animal and insulin not stated. Blood glucose values shown in mmol/l (non-US) measurements.) You see the cat above with one injection of Bovine (beef) Lente respond to the insulin, but that it simply does not last long enough for him/her. Without knowledge of the species of animal, species of insulin or other information, it is not possible to even speculate as to why the twice daily Lente insulin is not working. There's negligible response to the two Lente insulin shots given in the graph of the animal shown below, and it's provided as an example of resistance/lack of duration only. http://www.vin.com/ImageDBPub/TN20000/TN_IMC16199_550X0Y.jpg Duration By Species With regard to cats and dogs, the closest or perfect amino acid matches to their own native insulin (cats=beef) (dogs=pork) means faster onset, peak and shorter duration, all other things held equal. For both, use of r-DNA/GE/GM insulins would mean a slower onset, peak and a longer durationDuration of GE Insulin in Pets, due to these differences. It's just the reverse for people Duration of GE & Animal Insulins in HumansComparative of NPH (Isophane) Human & Porcine (Pork) Insulin in Diabetic Subjects-Diabetes Care-ADA-1982, with the r-DNA/GE/GM insulins acting and peaking faster and having less durationNew Patient & Transfer Studies-GE Duration Shorter Than Animal Insulins in Humans--Diabetes Care-ADA-1982 than either beef or pork insulin products Comparison of Pork & GE Insulin in Human SubjectsHuman & Porcine NPH (Isophane) Insulins Unequally Effective in Diabetic Patients-Acta Diabetologica Latina-1984Diabetes-World Mailing List Web Site-Questions About Insulin. Looking at the amino acid matches or differences, we can predict what they mean to duration for each. Dogs would have the shortest duration from pork insulin, slightly longer from r-DNA/GE/GM human insulin (one amino acid difference at insulin B chain, position #30), but longer from beefEvaluation of an Insulin Zinc Suspension for Control of Naturally Occurring Diabetes Mellitus in Dogs-Australian Veterinary Journal,-2000 (Page 3), with amino acid differences in 2 positions--insulin A chain positions #8 & #10. Cats would have less duration from beef insulin, as there is only the 1 amino acid difference there--the insulin A chain position #18. They would get more duration from pork insulin because there are 3 differing amino acids in the comparison. Longest lasting of all would be r-DNA/GE/GM human insulin--because none of the key amino acids matchBCP Veterinary Pharmacy--Bovine PZI InsulinComparison of 2 Ultralente Insulins With Protamine Zinc Insulin in Normal Cats-American Journal of Veterinary Research-1994. In humans, their longest-duration insulin would be beefDiabetes-World Mailing List Web Site-Questions About Insulin, due to the 3 amino acid differenceComparative Study of NPH (Isophane) Human Insulin & NPH (Isophane) Bovine Insulin in Human Subjects-Diabetes Care-ADA-1982. pork would have slightly more duration for them than r-DNA/GE/GM insulins, because of the 1 amino acid's differenceHuman & Porcine NPH (Isophane) Insulins are Unequally Effective in Diabetic Patients-Acta Diabetelogica-1984Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens-Hirsch-American Family Physician-1999. One injection of Bovine Ultralente insulin can last up to 40 hours when administered to a human--longer than Lantus; it is also peaklessUse of Beef Ultralente for Basal Insulin Delivery-Diabetes Care-American Diabetes Association-1986. When looking at extending duration in this way, one needs to realize that the amino acid differences produce antibodies; these antibodies are what prevents the insulin from being used so quickly. The possible drawback to extending duration by choosing insulins which are less akin to the native insulin of the diabetic is that the antibodies created by this may cause Insulin resistanceWSAVA 2001-Diabetes Mellitus: Treatment Options-Dr. David Bruyette. Since the antibodies indicate an immune system reaction, all the effects of an overstimulated immune system should be considered. When there is sufficient resistance, duration can decrease instead of increase; at that point, the effectiveness of the insulin is compromised. Insulin Amino Acid Differences Duration By Strength Comparing similar insulins with only strength differences means that the U100 strength insulin will have a slower onset, peak and longer duration than an insulin which is U40, U50 or even U80, which is available in some countriesThe Absorption of Subcutaneously Injected Short-Acting Soluble Insulin: Influence of Injection Technique & Concentration-Diabetes Care-ADA-1983, assuming the insulins are otherwise identicalAbsorption Comparison U40 & U100 Insulins-PubMedInsulin-Dependent Diabetes-Dr. Ragnar Hanas. An example of comparison for strength would be the 3 versions of 100% bovine PZI insulin available. Hypurin Bovine Protamine Zinc and Insuvet Protamine Zinc are both U100 insulins. BCP also produces a U100 version of its 100% beef PZI. All three would have the same length of duration. Switching strengths, however, changes things. Having BCP PZI in either U40 or U50 strength, as opposed to the BCP U100 PZI, Hypurin and Insuvet, means that the U40 and U50 strengths of the PZI BCP makes will have a faster onset, peak and less duration than the 3 U100 100% beef PZI insulins. The type of insulin is the same-PZI, the species is the same-beef. The hexamers of insulin tend to associate with each other (stay together); they cannot be readily absorbed while they remain this way. Diluting insulin into U40 strength forces them into dissociating (staying apart from each other, and becoming dimers and monomers), which means they are absorbedComparison of U100 and U40 Insulins-PubMedType 1 Diabetes Mellitus & Use of Flexible Insulin Regimens--Hirsch-American Family Physician-1999 better and more rapidly. An easy way to visualize this might be to think of a whole pie, slicing it into 6 pieces, then putting each piece on a separate plate. The pie can't be eaten until it's cut and everyone has a piece on his or her plate. The less strength an insulin has, the better it is absorbedInsulin Dependent Diabetes-Dr. Ragnar Hamas-1999 (Page 6)Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens--Hirsch-American Family Physician-1999. Better or faster absorption means a faster onset and peak but shorter duration. Using a less than U100 strength insulin is on the same principle as rapid-acting analog insulins. The analog insulins have their amino acid sequences altered to produce a faster onset and peak with shorter durationComparison of U40 & U100 Regular (Neutral) Insulin & Rapid-Acting Insulin Lispro (Humalog)-1998-PubMed. Diluting insulin from U100 strength does the same thing without altering the molecule. Knowing this, particularly in the case of cats, who are the primary users of PZI insulins, means that you can switch from a U40 or U50 insulin strength to U100 if duration is a problem and conversely, away from U100 to U40 or U50 if less duration or faster onset is needed--all without leaving bovine PZI. It is also possible to delay the absorption (thus increase the duration) of an insulin by increasing its strength. U500 insulin, which is five times more concentrated than U100, has been available through both Lilly and Novo Nordisk (Note: Their similar product is U400 strength insulinUse of U500 Insulin in Patients With Extreme Insulin Resistance-Diabetes Care-ADA-2005) by special order for many years. The insulin's main use is for people with extreme Insulin resistance, and is commercially available only in R/Neutral type. Though it is R/Neutral-type insulin, U400 & U500 insulins have a pharmacokinetic more like NPH insulin than U100 R/NeutralDiabetes World Mailing List Web Site-Questions About Insulin. Since there are no additives such as suspensions to alter R/Neutral insulin's action, the strength of the insulin formula hinders its breakdown into dimers and monomers, thus making it much slower-absorbed than U100 and lesser strength insulinsFive Fold Increase of Insulin Concentration Delays the Absorption of Human Insulin Injections in Pigs-Diabetes Research & Clinical Practice-2000Use of U500 R Insulin by Continuous Insulin Infusion (Insulin Pump)in Patients With Type 2 Diabetes & Severe Insulin Resistance Endocrine Practice-2006. In cases of severe insulin resistance, using a much higher concentration of insulin appears to "negate" the effects of immune-related Insulin resistance. The studies at the link below shows that there was no difference regarding antibodies when these patients were transferred from Iletin II NPH at U100 strength to a form of Iletin II R at U500 strength. However, the stronger insulin reduced their insulin needs from 33-75%U500 Insulin in the Treatment of Antibody-Mediated Insulin Resistance-Annals of Internal Medicine-1981Enhanced Efficacy of U500 Insulin in the Treatment of Insulin Resistance Caused by Target Tissue Insensitivity-American Journal of Medicine-1984. Whether the insulin is slowed by the size of its crystals, by its suspension, by the strength of its concentration, or has been designed to release slowly--all of these are different mechanisms with the same goal in mind--to keep the insulin in hexamer form (thus preventing its fast absorption) as long as possible. If you're having a hard time visualizing the role of strength regarding duration in an insulin, perhaps thinking of the following might help. If you had two stones, one which was pebble sized and the other which was somewhat larger, think about what it would take to break them down into small pieces with a hammer. It would take many more hammer blows to break the larger stone (U100 strength) into small pieces than for the pebble (U40 or U 50 strength); the duration of your work to shatter the larger one would be longer than for the smaller of the two. Further Reading *Absorption Kinetics of Regular, Isophane & Protamine Zinc Insulin in Normal Cats--Domestic Animal Endocrinology-1990 *Comparison of 2 Ultralente Insulin Preparations (Human & Beef/Pork) With Protamine Zinc Insulin (Beef/Pork) in Clinically Normal Cats-American Journal of Veterinary Research-1994 *Insulin Therapy in Cats With Diabetes Mellitus--JAVMA-1983 Contains peak, onset & duration information for NPH/isophane & PZI insulins in cats. *Pharmacology of a U40 Porcine Insulin in Cats-Journal of Feline Medicine & Surgery-2001-Drs. Rand & Martin Duration of Caninsulin/Vetsulin and Pork Actrapid (Pork R/Neutral-U100) data. References See also peak, onset, carryover and Insulin. Category:TermsCategory:TipsCategory:TreatmentsCategory:InsulinsCategory:Regulation